Tumour therapy in mice using adenovirus vectors expressing human TNFa.
Induction of systemic toxicity is a major factor limiting the use of TNFa in tumour therapy. The local expression of TNFa from Ad vector infected tumour cells, might result in reduced systemic toxicity and induce an enhanced local antitumour response. Two adenoviral vectors expressing human TNFa were constructed for use in tumour immunotherapy, one utilizing the HCMV promoter (Ad-HCMV-TNF) and the second utilizing the MCMV promoter (Ad-MCMV-TNF). Both vectors induced the secretion of hTNFa from transduced cells in vitro, however the MCMV promoter directed stronger expression in murine cells. Expression from the two vectors was also kinetically different with the MCMV promoter inducing earlier expression, from murine tumour cells in vitro and in vivo. Both vectors induced intratumoural necrosis, however only the Ad-MCMV-TNF vector induced systemic toxicity and significant antitumour activity when directly injected into tumours, killing 8 of 20 mice and inducing partial (2 of 12) and permanent (1 of 12) tumour regressions at a dose of 5x108 pfu/mouse. These data indicate that hTNFa expressed from an Ad vector is considerably toxic to mice while inducing a moderate antitumour response.
Marr
R A
RA
Department of Pathology, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4K1, Canada.
Hitt
M
M
Muller
W J
WJ
Gauldie
J
J
Graham
F L
FL
D000256:Adenoviridae; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000096:biosynthesis; D001681:Biological Assay; D002460:Cell Line; D002470:Cell Survival; D003587:Cytomegalovirus; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D007167:Immunotherapy; D007668:Kidney; D008325:Mammary Neoplasms, Experimental / Q000473:pathology / Q000628:therapy*; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D008546:Melanoma, Experimental / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008822:Mice, Transgenic; D009336:Necrosis; D011401:Promoter Regions, Genetic; D011994:Recombinant Proteins / Q000096:biosynthesis; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000494:pharmacology / Q000627:therapeutic use
D000952:Antigens, Polyomavirus Transforming; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha